PS1 mutations in humans invariably lead to an autosomal dominant form of early onset Alzheimer disease (AD). Transgenic mice expressing mutant PS1 increase the ratio of Abeta42/40, a hallmark of AD producing genes. We will study the PS1 and mutant PS1 transgenic mice developed in Core C, crosses with APP over-expressers (from Dr. Games) and PS1 null mice (from DR. Tonegawa). The 3 specific aims are to test the hypothesis that either a gain of function of PS1 or insufficiency of PS1 predisposes towards AD- like neuropathological changes, and to further explore the normal functions of PS1 or insufficiency of PS1 predisposes towards AD-like neuropathological changes, and to further explore the normal functions of PS1 and Notch/PS1 interactions. One of the strongest clues to PS1 function comes from the observation that a PS1 homologue in C elegans (sel-12) facilitates the function of lin-12, the C elegans homologue of the neurologic protein Notch. Sel-12 mutations in C elegans lead to an egg- laying defect that can be rescued with human PS1 or, less efficiently, with mutant PS1. Quite recently, two reports of PS1 knockout mice demonstrated severe developmental abnormalities, fetal or perinatal death, and alteration in Notch expression. One of the key answered questions about PS1 is, how do these observations of developmental changes relate to neurodegenerative changes in terminally differentiated neurons? We have attacked the problem of learning more about the functional roles of Notch and PS1 in post-mitotic neurons by developing a system that allows transfection of constitutively active Notch into primary neurons in culture. We have discovered that Notch robustly impairs or delays neurite outgrowth. This discovery shows a unique role for Notch activity even in terminally differentiated neurons, suggesting perhaps a role in neuroplasticity. Importantly, it also provides an assay to examine the interaction of PS1. We used this assay to test the hypothesis that over- expression of PS1 facilitates Notch function and preliminary data suggest that this is the case. We will now examine how this relates to mutant PS1, as well as physiologic interactors of endogenous Notch such as the inhibitor Numb. Taken together, this project aims at examining the neuropathological phenotypes of PS1 transgenic, and heterozygote PS1 null transgenic mice with age, to study the effect of these genetic manipulations on neural development; and to use primary neuronal cultures to examine the functional relationships between Notch and PS1 in vitro. These studies are central to the overall themes of the program project, and it is our belief that together these experiments will strengthen our understanding of the normal functions of PS1, and lead to insight into how PS1 dysfunction predisposes to AD.